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Familial forms are linked to germline loss-of-function mutations in CCM1\u20133, and sporadic lesions frequently harbour somatic gain-of-function mutations in MAP3K3 and PIK3CA. However, the mechanisms by which these somatic mutations drive lesion development remain incompletely understood, and no medical therapies are currently available.<\/jats:p>\n                  <jats:p>Here, we investigated the cooperative effects of MAP3K3I441M and PIK3CAH1047R mutations using transgenic neonatal and adult mouse models, supported by histology, micro-CT, bulk and single-cell RNA sequencing, and samples of human cerebral cavernous malformations.<\/jats:p>\n                  <jats:p>MAP3K3 I441M activated inflammatory and angiogenic transcriptional programmes in brain endothelial cells, whereas PIK3CAH1047R enhanced cell cycle and DNA replication pathways. Notably, MAP3K3I441M and PIK3CAH1047R double mutations synergistically amplified PI3K\u2013AKT\u2013mTOR signalling, inducing an \u2018angiogenic switch\u2019 reminiscent of tumour neovascularization. This interaction promoted endothelial angiogenesis and lesion development in mouse brains. Transcriptomic analyses of human cerebral cavernous malformations confirmed enrichment of angiogenesis-related gene signatures in double-mutation-related lesions. Treatment with the PI3K\u03b1-selective inhibitor alpelisib suppressed lesion formation and reversed pro-angiogenic signalling in both mouse models and patient-derived cerebral cavernous malformation organoids.<\/jats:p>\n                  <jats:p>These findings uncover a convergent mechanism involving MAPK and PI3K pathway activation in the pathogenesis of cerebral cavernous malformations and demonstrate that PI3K\u03b1 inhibition might offer a viable therapeutic strategy for a disease that currently lacks effective pharmacological treatment.<\/jats:p>","DOI":"10.1093\/brain\/awag017","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T12:44:32Z","timestamp":1768481072000},"page":"2860-2875","source":"Crossref","is-referenced-by-count":3,"title":["Angiogenic switching in cerebral cavernous malformations driven by MAP3K3\u2013PIK3CA synergy"],"prefix":"10.1093","volume":"149","author":[{"given":"Jian","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University , Beijing 100069 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqing","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University , Beijing 100069 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University , Beijing 100069 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daochao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chendan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University , Beijing 100053 ,","place":["China"]},{"name":"Department of Neurosurgery, China International Neuroscience Institute (China-INI) , Beijing 100053 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Liang","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Medicine, Capital Medical University , Beijing 100069 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gu","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Medicine, Capital Medical University , Beijing 100069 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